Project Summary Pain-related impairment of daily activities is a problem that impacts the quality of life of older adults. As the United states population ages, the rates of chronic analgesic use to treat pain-related depression of behavior in older adults increases. The magnitude of this problem has resulted in NIH prioritizing research examining how aging influences the experience and treatment of pain. A critical barrier to progress in improving the understanding and treatment of pain-related disruption of behavior in older adults is lack of consistency between clinical assessment of pain and the methods used to assess pain in preclinical research. Our goal is to improve treatment of clinically-relevant pain-related impairment of behavior in older adults by obtaining new knowledge on the role of aging in the expression, mechanisms, and treatment of pain using animal models of pain-related depression of behavior. Our central hypothesis is that pain-related dysfunction of dopamine (DA) systems that are important for motivated behavior is a key mechanism of pain-related depression of behavior in older adults. Our hypothesis is based evidence of age-related decreases in DA system activity, and our studies with adult rodents which found that 1) physiologically relevant pain stimuli depress behaviors that include feeding, locomotion and positively reinforced operant behavior, 2) impaired signaling in mesolimbic DA systems is implicated in pain-related depression of behavior, and 3) clinically effective analgesic drugs such as opioids block and reverse pain-related depression of both behavior and mesolimbic DA activity. Our objectives are to 1) model pain-related depression of behavior in aged male and female rats, 2) examine the role of aging in sensitivity to pain-related behavioral dysfunction, and 3) systematically examine determinants of opioid and monoamine uptake inhibitor effects on pain-related depression of behavior in an animal model of aging. Our outcomes will include 1) development and evaluation of a new approach for studying pain in older model organisms, 2) new knowledge of age-related mechanisms and predictors of the pain experience, 3) new knowledge of pain management strategies in aging, and 4) high impact research experiences for students. The impact of these studies will include new scientific information on age-related differences in the expression and mechanisms of motivational dimensions of pain, and determinants of effects of two classes of drugs, opioids and monoamine uptake inhibitors, on pain-related depression of behavior. Aim 1 will test the hypothesis that aging produces stimulus intensity-dependent changes in sensitivity to pain-related depression of behavior. Aim 2 will test the hypothesis that mu opioid agonist intrinsic efficacy and opioid exposure history are determinants of age-related differences in drug effects on pain-related depression of behavior. Aim 3 will test the hypothesis that age will mediate the potency and efficacy of monoamine reuptake inhibitors in an assay of pain-related depression of behavior.